title: SHP-2/PTPN11 mediates gliomagenesis  driven by PDGFRA and INK4A/ARF  aberrations in mice and humans.
abstract: Recent collaborative efforts have subclassified malignant glioblastomas into 4 clinical relevant subtypes based on their signature genetic lesions. Platelet-derived growth factor receptor α (PDGFRA) overexpression is concomitant with a loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) locus (encoding P16INK4A and P14ARF) in a large number of tumors within one subtype of glioblastomas. Here we report that activation of PDGFRα conferred tumorigenicity to Ink4a/Arf-deficient mouse astrocytes and human glioma cells in the brain. Restoration of p16INK4a but not p19ARF suppressed PDGFRα-promoted glioma formation. Mechanistically, abrogation of signaling modules in PDGFRα that lost capacity to bind to SHP-2 or PI3K significantly diminished PDGFRα-promoted tumorigenesis. Furthermore, inhibition of SHP-2 by shRNAs or pharmacological inhibitors disrupted the interaction of PI3K with PDGFRα, suppressed downstream AKT/mTOR activation, and impaired tumorigenesis of Ink4a/Arf-null cells, whereas expression of an activated PI3K mutant rescued the effect of SHP-2 inhibition on tumorigenicity. PDGFRα and PDGF-A are coexpressed in clinical glioblastoma specimens, and such co-expression is linked with activation of SHP-2/AKT/mTOR signaling. Together, our data suggest that in glioblastomas with Ink4a/Arf deficiency, overexpressed PDGFRα promotes tumorigenesis through the PI3K/AKT/mTOR-mediated pathway regulated by SHP-2 activity. These findings functionally validate the genomic analysis of glioblastomas and identify SHP-2 as a potential target for treatment of glioblastomas.
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Kun-Wei
authors.initials: KW
authors.lastname: Liu
authors.forename: Haizhong
authors.initials: H
authors.lastname: Feng
authors.forename: Robert
authors.initials: R
authors.lastname: Bachoo
authors.forename: Andrius
authors.initials: A
authors.lastname: Kazlauskas
authors.forename: Erin M
authors.initials: EM
authors.lastname: Smith
authors.forename: Karen
authors.initials: K
authors.lastname: Symes
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Hamilton
authors.forename: Motoo
authors.initials: M
authors.lastname: Nagane
authors.forename: Ryo
authors.initials: R
authors.lastname: Nishikawa
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
authors.forename: Shi-Yuan
authors.initials: SY
authors.lastname: Cheng
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D009154:Mutation; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000502:physiology*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019869:Phosphatidylinositol 3-Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11